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Cyclooxygenase-2 and stroke The long and short of it.

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Cyclooxygenase-2 and
Stroke: The Long and
Short of It
Prostaglandins (PGs) and thromboxanes (TXs) have
long been implicated in the pathogenesis of cerebral
ischemic stroke.1 However, because of the lack of appropriate investigative tools, their role in the mechanisms of the injury could not be clearly defined. The
identification and cloning of distinct forms of cyclooxygenase (COX), a rate-limiting enzyme for prostanoid synthesis, has provided new experimental approaches and has revived the interest in the role of
prostanoids in stroke and other brain diseases.2 In
this issue of Annals, Doré and colleagues,3 used transgenic mice overexpressing COX-2 selectively in neurons to investigate the involvement of this enzyme in
ischemic brain injury. They found that the brain
damage produced by temporary occlusion of the middle cerebral artery is exacerbated in COX-2 transgenic
mice, an effect associated with increased synthesis of
prostanoids. A selective COX-2 inhibitor attenuated
prostanoid synthesis both in wild-type and transgenic
mice. Unexpectedly, however, COX-2 inhibition reduced brain damage in wild-type mice, but not in
COX-2 transgenics. This surprising finding, while
providing additional evidence for the deleterious potential of COX-2, unveils a new aspect of role of
COX-2 in brain injury.
Three isoforms of COX have been identified:
COX-1, COX-2, and the COX-1 splice variant
COX-3.4 COX-1 and COX-2 have been studied most
extensively. COX-1 is constitutively expressed in
many organs and is thought to synthesize prostanoids
involved in normal cellular activities, such as gastric
secretion, endothelial function, and platelet aggregation.5 COX-2, although constitutively active in some
organs such as brain and kidney, is highly inducible
in response to a wide variety of stimuli including inflammatory mediators and growth factors.2 In brain,
COX-2 is normally present in glutamatergic synapses
and its expression and activity are regulated by synaptic activity.6 For example, COX-2 reaction products are involved in the increase in cerebral blood
flow produced by functional activation.7 In brain diseases such as ischemic stroke, COX-2 is transiently
upregulated, and its reaction products are thought to
contribute to tissue damage (Fig). COX-2–derived
prostanoids that could play a role include PGE2,
which enhances glutamate excitotoxicity, TXA2,
which promotes vasoconstriction and platelet aggrega-
tion, and PGJ2, a cyclopentenone prostaglandin that
induces postischemic apoptosis.8 –10 Furthermore,
COX-2–derived reactive oxygen species, mainly superoxide, also could play a role by producing oxidative stress.11 Therefore, the tissue damage resulting
from an acute increase in COX-2 activity results from
the concerted action of these factors. Accordingly,
pharmacological inhibition or genetic deletion of
COX-2 reduces the brain damage in models of focal
or global cerebral ischemia.12–14
On the other hand, if cerebral ischemia is induced
on a background of COX-2 overexpression, as in the
study of Doré and colleagues, the elevation in COX-2
reaction products, although greater than that observed
in wild-type mice, no longer contributes to the damage. Thus, the injury is not ameliorated by COX-2
inhibition. This finding adds a new twist to the
COX-2 story because it suggests that when COX-2 is
chronically upregulated the enhancement of ischemic
injury is independent of the increased catalytic activity of the enzyme. Perhaps, long-term COX-2 overexpression alters the susceptibility of the brain to
ischemic injury, a state of affairs that cannot be ame-
Fig. Hypothetical mechanisms of the effects of short- and longterm COX-2 upregulation on cerebral ischemic injury. Shortterm elevations in COX-2 expression or activity increase the
production of potentially toxic reaction products (PGE2,
TXA2, PGJ2, ROS) that then contribute to postischemic brain
injury. Long-term upregulation in COX-2 also worsens ischemic brain injury, but the postischemic surge of COX-2 reaction products is not involved in the pathogenic process. It is
hypothesized that COX-2 overexpression, through long-term
effects of its reaction products, triggers deleterious processes
(complement activation, ER stress, and CDK activation) that
are responsible for increased susceptibility to injury. This model
also may apply to brain diseases, such as Alzheimer’s and Parkinson’s disease, and amyotrophic lateral sclerosis, in which
there is chronic COX-2 upregulation. CDK ⫽ cyclindependent kinase; ER ⫽ endoplasmic reticulum; PGE2 ⫽
prostaglandin E2; PGJ2 ⫽ prostaglandin J2; ROS ⫽ reactive
oxygen species; TXA2 ⫽ thromboxane A2.
© 2003 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
liorated by short-term inhibition of COX-2 activity.
The mechanisms responsible for such increased susceptibility have not been elucidated in full, but there
are several possibilities (see Fig). The sustained increase in COX-2 reaction products in the transgenics,
while not sufficient to cause brain death, leads to
complement activation15 and to a proinflammatory
state that results in accumulation of misfolded proteins in the endoplasmic reticulum (ER stress).16,17
Furthermore, COX-2 transgenics exhibit activation of
cyclin-dependent kinases, which may promote neuronal apoptosis by abortive cell cycle reentry.18 Therefore, these pathogenic events could contribute to the
increased susceptibility to injury associated with longterm COX-2 overexpression.
A corollary of the findings of Doré and colleagues
is that the potentially deleterious mechanisms associated with long-term COX-2 overexpression also may
occur in human diseases in which there is chronic upregulation of COX-2, such as Alzheimer disease, Parkinson’s disease, or amyotrophic lateral sclerosis.19 –21
These alterations could render the brain more susceptible to insults deriving from other pathogenic factors,
such as A␤, glutamate excitotoxicity, and mitochondrial dysfunction. It is reasonable to assume that
chronic therapy with COX-2 inhibitors should counteract the long-term effects of COX-2 upregulation.
Studies addressing these issues are eagerly awaited.
Costantino Iadecola, MD
Division of Neurobiology
Department of Neurology and Neuroscience
Weill Medical College of Cornell University
New York, NY
DOI: 10.1002/ana.106682
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15. Spielman L, Winger D, Ho L, et al. Induction of the complement component C1qB in brain of transgenic mice with neuronal overexpression of human cyclooxygenase-2. Acta Neuropathol (Berl) 2002;103:157–162.
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19. Kitamura Y, Shimohama S, Koike H, et al. Increased expression of cyclooxygenases and peroxisome proliferator-activated
receptor-gamma in Alzheimer’s disease brains. Biochem Biophys Res Commun 1999;254:582–586.
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Vol 54
No 2
August 2003
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